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Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies

2000; Wiley; Volume: 9; Issue: 12 Linguagem: Inglês

10.1017/s096183680000331x

1469-896X

Andrew M. Petros, David G. Nettesheim, Yi Wang, Edward T. Olejniczak, ROBERT P. MEADOWS, JAMEY MACK, Kerry M. Swift, Edmund D. Matayoshi, HAICHAO ZHANG, CRAIG B. THOMPSON, Stephen W. Fesik,

Chemical Synthesis and Analysis

The three-dimensional structure of the anti-apoptotic protein Bcl-xL complexed to a 25-residue peptide from the death promoting region of Bad was determined using NMR spectroscopy. Although the overall structure is similar to Bcl-xL bound to a 16-residue peptide from the Bak protein (Sattler et al., 1997), the Bad peptide forms additional interactions with Bcl-xL. However, based upon site-directed mutagenesis experiments, these additional contacts do not account for the increased affinity of the Bad 25-mer for Bcl-xL compared to the Bad 16-mer. Rather, the increased helix propensity of the Bad 25-mer is primarily responsible for its greater affinity for Bcl-xL. Based on this observation, a pair of 16-residue peptides were designed and synthesized that were predicted to have a high helix propensity while maintaining the interactions important for complexation with Bcl-xL. Both peptides showed an increase in helix propensity compared to the wild-type and exhibited an enhanced affinity for Bcl-xL.